Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E

Fingar, Diane C.; Salama, Sofie R.; Tsou, Christina; Harlow, Ed; Blenis, John

doi:10.1101/gad.995802

Cited by 957 publications

(895 citation statements)

References 69 publications

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“…Transgenic T cells described here were also found to have increased rates of glycolysis, consistent with in vitro observations that Akt can promote increased nutrient uptake and glycolysis [35,42]. The mechanism of this increased resting T cell size is uncertain, but the PI3 K/Akt pathway has been shown to play an important role in cell size regulation in other cell types [43][44][45]. In addition, the Akt-induced increase in glucose metabo-lism can contribute to increased cell size directly by promoting the generation of metabolic substrates for biosynthesis, cell growth, and maintenance of increased biomass.…”

Section: Discussionsupporting

confidence: 84%

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

et al. 2003

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The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphatidylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoimmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity.

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Section: Discussionsupporting

confidence: 84%

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

et al. 2003

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“…Complete AKT activation depends on phosphoinositide-dependent kinase-1 4 (PDK1) and mTORC2, which phosphorylate AKT at two key sites: the activation loop (T308) and the C-terminal hydrophobic motif (S473), respectively (10,11). mTOR signaling is regulated through a network of feedback loops, protein partners, substrates, and regulators (12,13). Among them, PRAS40 (proline-rich AKT substrate 40 kDa) is a key regulator of mTORC1.…”

Section: Introductionmentioning

confidence: 99%

“…mTORC1 phosphorylates the hydrophobic motif of p70S6K on T389 (17). On the other hand, phosphorylation of 4E-BP1 at S65 by mTORC1 prevents the binding of 4E-BP1 to the eIF4E translation initiation factor activating capdependent translation (13).…”

Section: Introductionmentioning

confidence: 99%

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and Obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modelling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.3

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“…The mammalian target of rapamycin (mTOR), a 289 kDa Ser/Thr kinase, lies downstream of phosphatidylinositol 3 0 -kinase (PI3K), and senses mitogenic stimuli, nutrient conditions (Hara et al, 2002;Kim et al, 2002) and ATP (Dennis et al, 2001), and regulates multiple cellular events required for cellular growth (size) and proliferation (Fingar et al, 2002;Martin and Hall, 2005), differentiation (Erbay and Chen, 2001;Shu et al, 2002), and survival (Hosoi et al, 1999;Beuvink et al, 2005). Dysregulation of PI3K-mTOR pathway generates a favorable oncogenic environment and has been seen in a variety of transformed cells and human tumors, including rhabdomyosarcoma, lung, bladder, renal, ovary, breast, prostate, gastric, pancreatic, head and neck carcinomas, lymphoma, melanoma, glioma and other brain malignancies (Huang and Houghton, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…The data indicate that rapamycin is a potent inhibitor not only for cell proliferation, growth, and survival but also for cell motility. Studies have demonstrated that rapamycin inhibits proliferation and growth (size) by suppression of mTOR-mediated S6K1 and 4E-BP1/eIF4E pathways (Fingar et al, 2002;Bjornsti and Houghton, 2004;Fingar et al, 2004), induces apoptosis of cells through downregulation of mTOR-mediated 4E-BP1/eIF4E pathway , and inhibits differentiation of C2C12 cells in an mTOR-kinase activity-independent manner (Erbay and Chen, 2001), despite existence of controversy (Shu et al, 2002). However, the underlying mechanism of rapamycin inhibition of cell motility remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

et al. 2006

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Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), inhibits tumor cell motility. However, the underlying mechanism is poorly understood. Here, we show that rapamycin inhibited type I insulin-like growth factor (IGF-I)-stimulated motility of a panel of cell lines. Expression of a rapamycin-resistant mutant of mTOR (mTORrr) prevented rapamycin inhibition of cell motility. However, cells expressing a kinase-dead mTORrr remained sensitive to rapamycin. Downregulation of raptor or rictor by RNA interference (RNAi) decreased cell motility. However, only downregulation of raptor mimicked the effect of rapamycin, inhibiting phosphorylation of S6 kinase 1 (S6K1) and 4E-BP1. Cells infected with an adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6K1, but not with an adenovirus expressing wild-type S6K1, or a control virus, conferred to resistance to rapamycin. Further, IGF-I failed to stimulate motility of the cells, in which S6K1 was downregulated by RNAi. Moreover, downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) by RNAi-attenuated rapamycin inhibition of cell motility. In contrast, expression of constitutively active 4E-BP1 dramatically inhibited IGF-I-stimulated cell motility. The results indicate that both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell motility. Rapamycin inhibits IGF-I-stimulated cell motility, through suppression of both S6K1 and 4E-BP1/eIF4E-signaling pathways, as a consequence of inhibition of mTOR kinase activity.

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Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E

Cited by 957 publications

References 69 publications

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

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